The present invention is directed to bicyclic aryl and heteroaryl compounds which are opioid receptor modulators, e.g. mu-opioid receptor antagonists, that are useful for the treatment of metabolic disorders including obesity.
Obesity is characterized by an excessive adipose tissue mass relative to body size. Clinically, body fat mass is estimated by the body mass index (BMI; weight (kg)/height (m)2), or waist circumference. Individuals are considered obese when the BMI is greater than 30 and there are established medical consequences of being overweight. It has been an accepted medical view for some time that an increased body weight, especially as a result of abdominal body fat, is associated with an increased risk for diabetes, hypertension, heart disease, and numerous other health complications, such as arthritis, stroke, gallbladder disease, muscular and respiratory problems, back pain and even certain cancers.
Pharmacological approaches to the treatment of obesity have been mainly concerned with reducing fat mass by altering the balance between energy intake and expenditure. Many studies have clearly established the link between adiposity and the brain circuitry involved in the regulation of energy homeostasis. Direct and indirect evidence suggest that serotonergic, dopaminergic, adrenergic, cholinergic, endocannabinoid, opioid, and histaminergic pathways in addition to many neuropeptide pathways (e.g. neuropeptide Y and melanocortins) are implicated in the central control of energy intake and expenditure. Hypothalamic centres are also able to sense peripheral hormones involved in the maintenance of body weight and degree of adiposity, such as insulin and leptin, and fat tissue derived peptides.
There is a continuing need for novel antiobesity agents, particularly ones that are well tolerated with few adverse effects.
Mu-, kappa- and delta-opioid receptors have been implicated in a number of disease states and their modulation is a potential target for therapeutic intervention.
Antagonists of opioid receptors, in particular the mu-opioid receptor have been shown to reduce body weight in animal models of obesity (J. Zhang et al, European Journal of Pharmacology, 454 (2006) 147-152).
Antagonists of opioid receptors have thus been suggested as useful for the treatment of obesity and related disorders, and other diseases or disorders including substance abuse, alcohol abuse, compulsive gambling, depression, opiate overdose, septic shock, irritable bowel syndrome, nausea, vomiting and stroke.
International Patent Applications WO2004/026305 and WO2004/080968 describe diaryl ethers as opioid receptor antagonists.
There remains a need to provide further opioid receptor modulators for the treatment of diseases associated with opioid receptors, for example obesity.